In order to produce a desired pharmacological effect, a drug must be made available in appropriate concentrations at its site of action within the body. This availability is affected by numerous factors including the quantity of the drug administered, the rate of drug absorption, the distribution (binding or localization) within tissues, drug metabolism, and elimination from the body.
For orally administered drug dosage forms, drug absorption occurs within the gastrointestinal tract. While passing through the gastrointestinal tract, the drug should be released from the dosage form and be available in solution at or near the desired absorption site. The rate at which the drug is released from a dosage form and goes into solution is important to the kinetics of drug absorption. The dosage form and hence the drug is subjected to varying pHs during the transit, e.g., varying from about pH 1.2 (during fasting—but the stomach pH increases to as high as 4.0 after the consumption of food) to about 7.4 in other parts of the digestive tract (bile pH: 7.0-7.4 and intestinal pH: 5 to 7). Moreover, the transit time of the dosage form in different parts of the digestive tract may vary significantly depending on the size of the dosage form and prevailing local conditions. Other factors that influence drug absorption include physicochemical properties of the drug substance itself such as its pKa, solubility, crystalline energy, and specific surface area, as well as characteristics of the gastrointestinal tract itself, such as the properties of the luminal contents (pH, surface tension, volume, agitation and buffer capacity) and changes which occur following the ingestion of food. Consequently, it is often difficult to achieve drug release at constant rates.
Conventional oral dosage forms are often formulated as “immediate-release” dosage forms in which essentially the entire dose of drug is released from the dosage form within a very short period, e.g., minutes, following administration. Consequently, the plasma concentration of the drug typically rapidly rises to a peak concentration and subsequently declines as the drug is absorbed within tissues, metabolized, and/or excreted. The plasma concentration is generally characteristic of a particular drug due to the particular physical and metabolic properties of the drug. Generally, during some portion of the time period in which the plasma drug concentration rises, peaks and declines, the drug provides its therapeutic effects, i.e., when the plasma concentration of the drug reaches or exceeds the concentration required for clinical efficacy. If the plasma concentration is too high, undesirable side effects may occur, and when the plasma concentration of the drug drops below the clinically effective level, the therapeutic effects disappear.
Thus, in order to provide clinical efficacy while minimizing side effects it may be necessary to administer multiple doses of an immediate-release dosage form in order to maintain clinically effective plasma levels over the required period of time, while minimizing side effects due to excessive plasma levels.
Sustained or extended release dosage forms have been developed to minimize the number of doses administered in order to treat a particular condition. Sustained release dosage forms generally release the drug for an extended time period compared to an immediate-release dosage form. There are a number of different types of oral dosage forms that have been developed, including diffusion systems such as reservoir devices and matrix devices, dissolution systems such as encapsulated dissolution systems (including, for example, “tiny time pills”) and matrix dissolution systems, combination diffusion/dissolution systems, osmotic systems and ion-exchange resin systems as described in Remington's Pharmaceutical Sciences, 1990 ed., pp. 1682-1685.
Basic and acidic drugs exhibit pH-dependent solubility profiles varying by more than 2 orders of magnitude in the physiological pH range. For example, the weakly basic serotonin 5-HT3 receptor antagonist ondansetron hydrochloride is freely soluble in low pH gastric fluids, but it is practically insoluble at pH >6. Consequently, conventional once daily drug delivery systems such as matrix tablet formulations containing one or more dissolution rate controlling polymers or hydrophobic waxes, membrane coated monolithic or multiparticulate dosage forms, fail to release ondansetron in the relatively high pH environment of the intestinal tract, and are therefore unsuitable for once daily dosing.
Organic acids have been used to improve bioavailability, to reduce inter- and intra-subject variability, and to minimize food effects for weakly basic drugs. Multi-particulate dosage forms comprising weakly basic drugs to provide extended-release profiles are also described in the literature. These dosage forms are typically obtained by granulating or layering the drug with one or more organic acids and then coating the resulting particles with an extended release coating. However, such dosage forms are not suitable for once-daily dosing because they fail to maintain a sufficiently high plasma concentration of the drug, at least in part because the release of the organic acid is not sufficiently prolonged to provide enhanced dissolution of the weakly basic drug. Furthermore, in these compositions the weakly basic drugs can form varying levels of salts with the organic acids during processing and storage, which may affect the drug release properties.